Chemotherapeutic drug-triggered AEP-cleaved G3BP1 orchestrates stress granules/nucleoli/mitochondria in osteosarcoma

Abstract

Osteosarcoma (OS) is the most frequent primary bone sarcomas with high recurrence and poor prognosis. Emerging evidence indicates that membraneless organelles stress granules (SGs), whose assemblies are driven by scaffold protein G3BP1, are extensively involved in tumor, especially in OS. However, how SGs behave and communicate with organelles, particularly nucleoli and mitochondria, during drug challenges remain unknown. This study revealed that chemotherapeutic drugs activated the cysteine protease asparagine endopeptidase (AEP) to specifically cleave the SG core protein G3BP1 at N258/N309 in OS and malignant glioma. tG3BP1-Ns modulated SG dynamics by competitively binding to full-length G3BP1. Strikingly, tG3BP1-Cs, containing a conserved RNA recognition motif CCUBSCUS, sequestered mRNAs of ribosomal proteins and oxidative phosphorylation genes in the nucleoli and mitochondria to repress translation and oxidative stress. Moreover, the inhibition of AEP promoted the tumor-suppressing effect of chemotherapeutic drugs, whereas AEP-cleaved G3BP1 rescue reversed the effect in both OS and glioma models. Cancerous tissues exhibited high levels of AEP and G3BP1 truncations, which were strongly associated with poor prognosis. Accordingly, this study proposed a new paradigm and potential therapeutic targets to address chemotherapy sensitivity conferred by AEP-cleaved G3BP1-mediated SGs/nucleoli/mitochondria coordination.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(81772654)

Shanghai Association for Science and Technology (Shanghai Association for Science & Technology)(201409003000)

the National Key R&D Program of China, 2024YFB3213200 Topic No. 2024YFB3213204

the National Key R&D Program of China, grant number 2023ZD0502206 the National Key Research and Development Program of China, grant number 2022YFC2404602 Scientific and Technological Innovation Action Plan of Shanghai Science and Technology Committee, grant number 22Y31900103 Beijing Science and Technology Innovation Medical Development Foundation, grant number KC2021-JX-0170-9)

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